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4 Cangelosi GA, Freeman RJ, Lewis KN, et al. Evaluation of a high-throughput repetitive-sequence-based PCR system for DNA finger-printing of Mycobacterium tuberculosis and Mycobacterium avium

complex strains. J Clin Microbiol 2004; 42: 2685–2693.5 van Ingen J, Boeree MJ, Kosters K, et al. Proposal to elevate

Mycobacterium avium complex ITS sequevar MAC-Q toMycobacterium vulneris sp nov. Int J Syst Evol Microbiol 2009; 59:2277–2282.

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mycobacteria to the species level by polymerase chain reaction

and restriction enzyme analysis. J Clin Microbiol 1993; 31: 175–178.

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Am Rev Respir Dis 1979; 119: 107–159.

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mycobacterial pulmonary infection in a group of hospitalizedpatients in Chicago. II. Demographic studies. Am Rev Respir Dis

1965; 91: 592–595.

DOI: 10.1183/09031936.00096312

Successful treatment of progressive diffuse

PEComatosisTo the Editors:

A 43-yr-old, nonsmoking female undergoing gynaecologicalsurgery for menorrhagia was noted to have reduced arterialoxygen saturation and, on direct questioning, reported long-standing, mild, exercise-limiting dyspnoea. Treatment withinhaled bronchodilators had had no effect on her symptoms.Over the succeeding 2 yrs she developed progressive dyspnoeawith corresponding deterioration in exercise tolerance. At thattime, standard section computed tomography (CT) showeddiffuse changes that were considered nonspecific, consisting ofdifficult-to-characterise opacities without zonal predominance;specifically, there were no conspicuous cysts. The features weresuggestive of an infiltrative process and lung function assess-ment disclosed a forced expiratory volume in 1 s (FEV1) of2.12 L (80% predicted), forced vital capacity (FVC) of 2.66 L(88% pred) and transfer factor of the lung for carbon monoxide(TL,CO) of 49% pred. A surgical lung biopsy was performed.Ultrasound of the kidneys disclosed no abnormality; specifi-cally, there was no evidence of angiomyolipoma.

Lung histology showed an interstitial proliferation of cytolo-gically bland, mainly rounded cells with predominantly clearcytoplasm (fig. 1a) and without obvious mitotic activity. Inareas, these cells formed nodules in the alveolar parenchyma,while elsewhere, the proliferation was more diffuse. Focally,the cells showed a more spindled morphology, having blunt-ended nuclei and moderate volumes of eosinophilic cytoplasm(fig. 1b), a characteristic of lymphangioleiomyomatosis (LAM).All cells were positive for smooth muscle actin (SMA) anddesmin, with focal positivity for HMB45. They were alsopositive for progesterone and oestrogen receptors. A periodicacid–Schiff stain for glycogen was focally positive. Followingclinicopathological review, it was felt that the lack of imagingfeatures characteristic of LAM, the lack of S-100 positivitycharacteristic of a clear-cell sugar tumour (CCST) and theoverall perivascular epithelioid cell (PEC)omatous phenotypemeant the case was best described as diffuse PEComatosis.

Because of the overlap between LAM and PEComatousdisorders, treatment with hydroxyprogesterone was started.

Genotyping for tuberous sclerosis was undertaken and provednegative. After 18 months of treatment, the patient’s exercisetolerance had deteriorated further, and she also reporteddevelopment of swelling of her left leg extending up to thegluteal region. Her lung function had deteriorated, with an FEV1

of 1.58 L (63% pred), FVC of 2.03 L (70% pred) and TL,CO of3.43 L (43% pred). CT showed interlobular septal thickening, awidespread micronodular pattern and a right-sided pleuraleffusion, subsequently confirmed to be chylous, but again nocysts (fig. 1c). CT of the abdomen and pelvis showed largeretroperitoneal paraortic lesions of fluid density that, on biopsy,were shown to be lymphatic in nature. Lymphangiographyshowed decreased inguinal lymph drainage with dilatation of thepelvic lymphatic system. Following biopsy, significant chylousascites developed. Because of the rapid clinical deterioration,combined with the lymphatic abnormalities, chylous pleural andabdominal effusions, a multimodal approach to therapy wasadopted. The patient was commenced on: sirolimus (Rapamune,Wyeth, NJ, USA), at an initial dose of 0.25 mg?m-2 body surfacearea, increased over a period of 4 months to achieve serumsirolimus levels of 10–15 ng?mL-1; subcutaneous octreotide(100 mg three times daily); and a medium-chain triglyceride(MCT) diet (aiming for a dietary fat content of ,14 g?day-1).

At review, 3 months after the initiation of this therapy, therehad been a dramatic improvement in symptoms withimproved exercise tolerance and virtual resolution of lowerlimb oedema, chylous ascites and pleural effusion (fig. 1d).Lung function tests disclose a marked improvement in bothspirometry (FEV1 2.26 L, 91% pred; FVC 2.97 L, 102% pred)and TL,CO (51% pred). The patient remained clinically andradiographically stable 24 months after stopping octreotideand having relaxed the MCT diet. She continues on sirolimuswith target serum levels of 5–10 ng?mL-1.

The clinical presentation in this case is suggestive of LAM.However, in typical cases, spirometry shows an obstructivedefect with widespread pulmonary cysts [1], while this patientpresented with restrictive disease and no cysts. The presence ofmultiple nodules and an interstitial proliferation of cells withstriking epithelioid/clear cell morphology are more character-

1578 VOLUME 40 NUMBER 6 EUROPEAN RESPIRATORY JOURNAL

istic of a CCST (or PEComa) involving the lung. However,PEComas of the lung are typically solitary and stain preferen-tially with S-100 rather than SMA and desmin. This case,therefore, lies within the spectrum of LAM and multiplePEComas within the lung, lesions viewed as clinically distinctbut now known to be characterised by co-expression ofmyogenic and melanogenesis-related markers as well as geneticalterations related to the tuberous sclerosis complex [2, 3].However, review of the literature shows no cases with thisphenotype, although there are rare cases with overlappingfeatures of LAM and CCST in females of reproductive age, oneof whom also had multifocal micronodular pneumocytehyperplasia and one of whom had tuberous sclerosis [4, 5]. Afurther two patients were found incidentally to have cysticchanges, characteristic of LAM, and interstitial nodules on high-resolution CT, with histology showing a PEComatous prolifera-tion, one patient again having tuberous sclerosis [6]. Finally, onecase of localised cystic change with an associated nodule

showed a CCST and coexistent LAM [7]. In three out of fivepatients, there was no progression outside the lung over 15 yrs[6, 7]. All published cases, therefore, contrast with this case inwhich there was no cystic disease and significant pulmonaryand extrapulmonary progression over 18 months. Disease inthis patient appeared to progress as a diffuse process rather thanmetastasise (as in the context of a malignant CCST), as therewere no histologically malignant features and progression wascontinuous between anatomical compartments. Furthermore,the response to therapy was not that of a malignant condition.

The rationale for treatment in our patient was two-fold.Chylous ascites and pleural effusions were causing significant,debilitating symptoms that had necessitated prolonged hospi-talisation. Furthermore, over serial visits, there was clinical,radiographic and physiological evidence of potentially fataldisease progression. The treatment approach chosen wasintended to address both the PEComatous proliferation, and

c) d)

a) b)

FIGURE 1. Diffuse PEComatosis. a) Many of the nodules comprise cytologically bland, clear cells, while b) focally, the cells show a more spindled morphology with the

nuclei being blunt-ended and containing moderate volumes of eosinophilic cytoplasm characteristic of lymphangioleiomyomatosis. Haematoxylin and eosin. Magnification:

6200 c) Computed tomography (CT) 18 months after diagnosis showed marked interlobular septal thickening in the upper lobes, a probable micronodular pattern (on this

thick CT section) and a right-sided pleural effusion, but no cystic air spaces. d) 3 months later there was an improvement with less thickening of the interlobular septa (a

micronodular pattern persists) and almost complete resolution of the right pleural effusion.

cEUROPEAN RESPIRATORY JOURNAL VOLUME 40 NUMBER 6 1579

the lymphatic leakage and chylous effusions. The exactaetiology of the chylous effusions is unclear, but is likely tohave been a consequence of damage to dilated, tortuous intra-abdominal and intrathoracic lymphatics. MCT diet has beensuccessfully used to treat a variety of disorders, includingprimary lymphangiectasia, traumatic chylous duct injury andrecurrent chylous effusions in LAM [8]. Octreotide, a somatos-tatin analogue, has been used with variable success in a variety ofchylous disorders [9]. Although the mechanism of action ofoctreotide is unclear, it is believed to prevent splanchnicvasoconstriction and inhibits absorption of triglycerides, thusreducing lymphatic flow. Sirolimus is an inhibitor of mTOR(mammalian target of rapamycin). Aberrant activation of mTORis central to the pathogenesis of LAM, with alterations in themTOR pathways also seen in other PEComatous entities [3].Clinical trials of sirolimus have demonstrated that, in femaleswith LAM or tuberous sclerosis, sirolimus is effective in shrinkingabdominal angiomyolipomas and in preventing progression ofpulmonary disease [10]. In our patient, it is impossible to know,without repeat biopsy, whether the principal benefit of treatmenthas been to reduce lymphatic leakage or whether there has, infact, been regression of the PEComatosis.

In conclusion, diffuse PEComatosis should be added to thespectrum of entities characterised by PEC differentiation.Furthermore, it should be appreciated that PEComatosis canbe progressive both within and outside the lungs. Finally, thiscase highlights sirolimus and strategies that reduce lymphaticflow as therapies that are effective in the treatment of diffusePEComatosis.

Kay Lawson*, Toby M. Maher*,", David M. Hansell",+ and

Andrew G. Nicholson*,"

*Dept of Histopathology, Imperial College, #Interstitial Lung

Disease Unit, Imperial College, "Royal Brompton and

Harefield Hospitals NHS Foundation Trust, and National

Heart and Lung Institute, Imperial College, and +Dept of

Imaging, Imperial College, London, UK.

Correspondence: A.G. Nicholson, Dept of Histopathology,

Royal Brompton Hospital, Sydney St, London SW3 6NP, UK.

E-mail: a.nicholson@rbht.nhs.uk

Statement of Interest: None declared.

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